aldosterone in metabolic...

The Jounal of Clinical InvestigationVol. 46, No. 10, 1967

Aldosterone in Metabolic Alkalosis *JEROMEP. KASSIRER, FREDERICKM. APPLETON, JOSEPHA. CHAZAN,AND

WILLIAM B. SCHWARTZt(From the Department of Medicine, Tufts University School of Medicine and the Renal

Laboratory, NewEngland Medical Center Hospitals, Boston, Massachusetts)

Abstract. Studies have been carried out in human volunteer subjects toevaluate the role of aldosterone in the development, maintenance, and cor-rection of metabolic alkalosis induced by selective depletion of hydrochloricacid. During the first phase of our study the rate of aldosterone secretionwas measured before the induction of alkalosis (while the subjects were on alow salt diet) and again after a steady state of metabolic alkalosis had beenestablished. The data demonstrate a fall in aldosterone secretion from avalue of approximately 500 ptg/day to a value of approximately 200 pAg/day.Thus, it appears that an increased rate of aldosterone secretion is not a pre-requisite to the elevation of the renal bicarbonate threshold.

During the second phase of our study, aldosterone was administered to thealkalotic subjects in doses of 1000 ug/day (or deoxycorticosterone acetate indoses of 40 mg/day) in order to determine the effects of a persistent steroidexcess on the ability of sodium chloride to correct the acid-base disturbance.The data demonstrate that despite the administration of steroid, the ingestionof sodium chloride led to a reduction in plasma bicarbonate concentrationfrom 39 to 29 mEq/liter, accompanied by a suppression of renal acid excre-tion. This reduction in plasma bicarbonate concentration occurred withouta concomitant retention of potassium, a deficit of as much as 400-500 mEqof potassium persisting during repair of the acid-base disturbance. Our find-ings suggest that "saline-resistant" alkalosis, when it occurs in the absenceof primary hyperadrenalism, cannot be attributed to aldosterone excess and/orpotassium depletion of the magnitude seen in our study. Wealso suggestthe need for a reappraisal of the way in which aldosterone excess contributesto the genesis and maintenance of alkalosis in primary aldosteronism.

Introduction

It is well recognized that patients with primaryaldosteronism often have metabolic alkalosis and itis widely believed that the steroid excess per se

* Received for publication 27 March 1967 and in re-vised form 19 June 1967.

This study was supported in part by grants H-759 andHTS-5309 from the National Heart Institute, PublicHealth Service Grant FR-54, General Clinical ResearchCenters Branch, National Institutes of Health, TheAmerican Heart Association, and the Samuel Bass Fundfor Kidney Research.

i Address requests for reprints to Dr. William B.Schwartz, New England Medical Center Hospitals, 171Harrison Avenue, Boston, Mass. 02111.

plays a central role in the genesis and main-tenance of the alkalotic state. There are, however,several observations which raise questions concern-ing this interpretation. First, many patients withprimary aldosteronism and high rates of aldos-terone secretion do not develop alkalosis (1-3)and second, it has proved difficult to produce morethan a slight elevation of bicarbonate concentra-tion in normal man given large doses of an adrenalsteroid such as deoxycorticosterone acetate(DOCA) (4, 5).

Wehave undertaken exploration of the role ofaldosterone in metabolic alkalosis in man, using asa model the experimental alkalosis induced by se-lective depletion of hydrochloric acid (6, 7). Two

1558

ALDOSTERONEIN METABOLICALKALOStS

approaches were used. First, aldosterone secre-tion rates were measured in normal human sub-jects before and after the induction of metabolicalkalosis. Second, aldosterone or DOCAwas ad-ministered to the alkalotic subjects in order to de-termine if an excess of salt-active steroids wouldprevent correction of the alkalosis by sodium chlo-ride (8, 9). The data indicate that an increasedrate of aldosterone secretion is not a prerequisitefor the development or maintenance of metabolicalkalosis and suggest that secondary aldosteronismis not responsible for the development of "saline-resistant" alkalosis.

Methods

Balance studies of 37-54 days' duration were carriedout on the Clinical Study Unit of the New EnglandMedical Center Hospitals on nine healthy male volun-teers ranging in age from 21 to 38 yr. The subjectswere accepted for study only if there had been no recenthistory of significant illness, if the findings on physicalexamination were within normal limits, and if the hemo-globin concentration, white blood cell count, serum cre-atinine concentration, chest X-ray, electrocardiograph,and findings on urine analysis were all within normallimits.' During each study the subjects consumed aconstant diet, normal in composition except for its lowsodium and chloride content. The composition of thedaily diet, which was determined by analysis of two du-plicate diets from each study, varied among subjects asfollows: sodium 4-7 mEq, potassium 55-86 mEq, chlo-ride 4-8 mEq, and nitrogen 8.1-9.9 g. The daily fluidintake was chosen by each subject and maintained at aconstant level throughout the study; it varied between1900 and 2900 cc among the subjects. Seven subjectswere given an oral supplement of 40 mmoles of sodium perday as neutral phosphate (Na2HPO4: NaH2PO44:1) be-ginning either during the control period or immediatelyafter the period of gastric drainage. Two subjects re-ceived no sodium phosphate supplement.

Metabolic alkalosis was induced by selective depletionof hydrochloric acid according to a technique describedelsewhere (6). Briefly summarized, after a 5 day controlperiod, drainage of the stomach under Histalog stimula-tion was undertaken each night (in the post absorptivestate) during 2-7 nights ("gastric drainage period").

1 In one additional subject (J.M.) rheumatic heart dis-ease with mitral stenosis was not initially recognized butthe diagnosis was made later when, during sodium chlo-ride administration, pulmonary congestion developed andthe cardiac auscultatory findings became more promi-nent. Standard therapeutic measures resulted in promptand complete recovery from the circulatory congestion.The results of this study were identical with those in theother subjects (Table I) except for a greater sodiumchloride retention.

Fluid and all electrolytes other than hydrochloric acidwere replaced on the day after drainage by adding ap-propriate quantities of sodium chloride, potassium chlo-ride, and water to the usual intake.

Data obtained during the development of alkalosis andduring the 4-7 days after drainage was discontinued (thepostdrainage period) were virtually identical with thosepreviously described (6), and are given in Table I.Thereafter, each study was divided into three periods: (a)a period of aldosterone or DOCAadministration (here-after referred to as the "steroid period"), (b) a periodin which steroid administration was continued and sodiumchloride was added to the daily diet ("steroid plus saltperiod"), and (c) a final period in which steroid ad-ministration was discontinued but sodium chloride intakewas continued ("poststeroid period").

Steroid periodSteroids were given for 5-7 days according to one of

the following three schedules: (a) d-aldosterone insesame oil, 1000 Ag/day in six divided doses at 4-hr in-tervals (two subjects), (b) d-aldosterone in sesameoil, 1000 /Ag/day in three divided doses at 8-hr intervals(three subjects), or (c) deoxycorticosterone acetate(DOCA) in oil, 40 mg/day in two divided doses at 12-hrintervals (four subjects). One of the two subjects whodid not receive the sodium phosphate supplement re-ceived aldosterone on the 8 hr schedule; the other re-ceived deoxycorticosterone acetate.

Steroid plus salt periodDuring this period the constant diet was continued but

all subjects were given a dietary supplement of 2 mmolesof sodium chloride per kg until a new steady state ofacid-base equilibrium had been achieved; 7-10 days wererequired to achieve this new steady state. The observa-tions were continued for an additional interval of 5-10days in five of the patients (only 1-3 days in the others)in order to determine whether continued steroid ad-ministration would lead to a late change in acid-base orelectrolyte equilibrium.

Poststeroid periodSteroid administration was discontinued and the daily

sodium chloride supplement was continued unchanged.Observations were carried out for periods ranging from3 to 16 days. It was possible to achieve full restorationof normal potassium equilibrium in only a few of thesubjects because many were not willing to continue in-gesting the same diet for a longer period.

The experimental procedures, analytical methods, andbalance data calculations were identical with those previ-ously described (6, 8).

Aldosterone secretion studiesAldosterone secretion studies were carried out in

four of the nine subjects shown in Tables I and III aswell as in an additional subject (G.C.) in whom, subse-quent to the secretion studies, a different experimental

i559

tASSIktR, APPLEION, CHAZAN, AND SCHWARTZ

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ALDOSTERONEIN METABOLICALKALOSIS

protocol was followed. Observations were made on thelast day of the control period and were repeated on thelast day of the postdrainage period. After injection of5 uc of tritiated aldosterone, the urine was collected forthe succeeding 24 hr and aldosterone secretory rateswere determined. The methods used for these deter-minations have been described elsewhere (10). The re-

sults of these studies are given in Table IV.

Results

Balance data for all nine subjects are shown inTable I. At the end of the postdrainge period,i.e., immediately before the steroid period, theaverage cumulative balances for chloride were

- 249 mEq, sodium - 33 mEq, potassium - 251

-LOWCHLORIDEDIEr(7mmoles/dayJ b

I. ...,,... ...................... .............

IALDOSTERONE 1L.1l1,lilli 1-0 mg/day IIIIIIIIIU

V7/'//A/NaCI 135mnmoles /davy7////A40

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30

110

100

900

-100

-200

-300

+1500

*1000

+500

10

500

0

I..1- -500

I . I I0 6 12 18 24 30 36 42

DAYSFIG. 1. PLASMA COMPOSITION AND ELECTROLYTEBALANCEIN A REPRESENTATIVESTUDY DESIGNED TO

EVALUATETHE INFLUENCE OF ALDOSTERONEON THE CORRECTIONOF GASTRIC ALKALOSIS BY ADMINISTRA-

TION OF SODIUM CHLORIDE (SUBJECT L.B.). Note that the scale used in plotting potassium balance is

different from that used for sodium and chloride.

|GASTRIC

I \i

I,

40F

HCO3mEq/ liter

35

30

110

mEq/liter 00

900

K -100-200

(corr.for N)-300

+1500

Na +1000

+ 500 _

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KASSIRER, APPLETON, CHAZAN, AND SCHWARTZ

TABLE II

Balance data on representative study (subject M. L.)

Intake UrineBody

Day weight Fluid Na* Cl K N Vol pH HCOs Cl Na

mEq g45 5 76 8.145 5 76 8.145 5 76 8.145 5 76 8.145 5 76 8.1

ml mEq1735 6.54 8 16 521950 6.42 7 11 412095 6.59 9 8 411730 6.46 7 6 - 331970 6.64 8 6 44

Gastric drainage 611 66.8 2200¶ 45711 66.1 2200 45811 65.8 2200 45911 65.6 2200 45

Postdrainage

DOCA,40 mgdaily

DOCA,40 mgdaily plus NaCI

NaCI, poststeroid

10 65.811 65.512 65.513 65.314 65.115 65.0

16 64.817 64.518 64.419 64.120 63.921 63.7

222324252627282930.3132333435363738

3940414243444546474849505152535455

64.364.765.265.665.766.467.167.367.467.267.267.166.866.666.566.566.2

65.965.165.164.364.064.163.863.763.763.363.062.862.662.462.261.962.0

220022002200220022002200

220022002200220022002200

22002200220022002200220022002200220022002200220022002200220022002200

2200220022002200220022002200220022002200220022002200220022002200

5 76 8.15 76 8.15 76 8.15 76 8.1

45 5 76 8.145 5 76 8.145 5 76 8.145 5 76 8.145 5 76 8.145 5 76 8.1

45 5 76 8.145 5 76 8.145 5 76 8.145 5 76 8.145 5 76 8.145 5 76 8.1

174 133 76 8.1174 133 76 8.1174 133 76 8.1174 133 76 8.1174 133 76 8.1174 133 76 8.1174 133 76 8.1174 133 76 8.1174 133 76 8.1174 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1

173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1173 133 76 8.1

1770 6.78 152340 7.00 261800 7.01 272540 7.05 41

2200 6.66 172320 6.66 191810 6.66 152075 6.63 122050 6.67 161960 6.68 17

2170 6.59 131995 6.52 92285 6.67 142078 6.56 101960 6.59 92145 6.61 11

5 532 671 601 69

1 391 461 401 411 441 49

1 241 121 131 71 71 10

1430 6.56 7 11280 6.72 6 11390 6.80 13 21100 6.87 16 41410 7.09 19 21920 7.07 24 25

1290 7.22 31 511510 7.18 25 481750 7.17 34 821640 7.18 27 1021700 7.08 29 1111795 7.04 25 1081810 7.05 33 1341890 7.04 24 1271585 7.13 29 1601645 7.13 26 1232000 7.07 31 130

1795 7.23 41 1332400 7.37 65 2071650 7.07 28 1562450 7.22 48 1981975 7.03 30 1441610 6.94 18 1222170 7.14 33 1611780 6.85 16 1301900 6.89 19 1472170 6.94 23 1691720 6.90 19 1201750 6.89 20 1661910 6.92 18 1341950 6.89 18 1531695 6.83 14 1402025 6.99 24 156

1562

Controlkg

1 68.52 68.33 67.94 67.85 67.7

ml22002200220022002200

91223376878

10698

130151155129150141165133144

210323238301231193247204218239187222189195184201

* The sodium intake of S mEq/day was supplemented by 40 mEqof sodium (as neutral phosphate) throughout the study.$ TA, titratable acid.

Calculated as NH4 + titratable acid - HCOs.The Na and K removed in the gastric juice was replaced by administration of an equivalent amount of NaCl and KCI. On day 6,59

mEq of hydrochloric acid was removed from the stomach; on day 7, 81 mEq; on day 8, 65 mEq; and on day 9, 79 mEq.¶ Intake figures do not include values for fluid and electrolytes given to replace the quantities removed the previous day by gastric aspiration.

ALDOSTERONEIN METABOLICALKALOSIS 1563

TABLE ii-( Continued)Balance data on representative study (subject M. L.)

Urine Stool PlasmaHemato-

K NH4 TAI PO Net acidi N Na Cl K N pH HCO. Na K Cl Creatinine crit

mEq80 2782 2688 1882 2684 23

95 11103 1198 8

116 7

m/moles mEq21 47 3922 46 4119 46 2822 46 4218 47 33

15 47 1110 47 - 58 43 -119 48 -24

100 21 21 51 2489 21 20 49 2181 24 18 44 2782 24 19 46 3179 24 17 43 2586 23 20 50 26

94 24 20 45 3197 25 20 42 37

110 24 19 48 29108 23 20 43 33106 22 19 44 32107 23 19 46 31

96 15 20 43 2887 21 13 34 2875 20 10 29 1771 17 9 30 1060 18 5 32 554 15 5 29 -561 19 3 30 -965 23 3 33 175 27 4 33 -377 24 5 41 282 35 7 43 1376 37 6 35 1880 42 6 32 1571 41 6 32 2372 43 3 25 1770 45 4 29 2383 45 5 33 19

g mEq12.5 1. 1 712.3 1 1 712.2 1 1 711.4 1 1 710.8 1 1 7

10.4 1 0 110.3 1 0 110.4 1 0 111.2 1 0 1

11.410.210.311.010.511.2

11.111.211.410.810.010.1

9.39.58.16.97.26.38.07.78.17.27.77.76.57.06.56.47.2

1

111

11

1111

g1.01.01.01.01.0

0.20.20.20.2

mEq/liter7.40 28.7 1337.35 29.0 136

7.39 30.8 1377.39 29.8 144

mg/100 ml4.2 105 1.14.5 102 1.1

4.7 101 1.13.9 98 1.0

7.45 34.8 147 3.5 95 1.07.43 36.8 143 3.4 93 1.37.49 38.4 142 3.0 90 0.9

1 3 0.6 7.48 38.81 3 0.61 3 0.6 7.45 38.71 3 0.6 7.46 38.81 3 0.6 7.44 36.81 3 0.6 7.48 36.9

1 3 0.6 7.45 37.21 3 0.61 3 0.6 7.46 40.21 3 0.6 7.48 40.31 3 0.6 7.46 40.01 3 0.6 7.43 40.9

0 1 10 1.5 7.48 38.10 1 10 1.50 1 10 1.5 7.49 37.30 1 10 1.50 1 10 1.5 7.48 32.60 1 10 1.5 _ 7.43 33.20 1 10 1.5 7.45 31.60 1 10 1.5 7.39 30.50 1 10 1.5 7.44 31.21 1 11 1.6 7.44 30.31 1 11 1.6 7.45 30.01 1 11 1.6 7.40 30.21 1 11 1.61 1 11 l.6 7.45 29.91 1 1 1 1.6 7.42 30.81 1 11 1.6 7.45 29.91 1 11 1.6 7.43 30.1

141 3.2 89 0.9

139 3.1 88 0.9140 3.6 89 1.1140 3.1 91 1.1138 2.9 91 1.0

139 3.2 89 1.1

141 3.1 90 1.0140 2.6 89 1.1141 2.7 92 1.1140 2.6 91 1.1

144 2.8 95 1.0

145 3.0 101 1.0

148 3.0 106 1.1148 3.0 107 1.0146 3.0 106 1.0146 3.1 106 1.0146 3.4 108 1.0146 3.3 108 1.0145 3.2 108 1.0145 3.1 107 1.1

146 2.9 108 1.1145 3.2 107 1.0145 2.9 106 1.0146 3.0 107 1.0

40 31 2 2818 29 1 3113 22 6 3416 29 3 3613 24 6 3614 23 7 3417 25 4 3521 22 10 3722 23 9 3632 22 7 3328 20 8 3641 23 8 3445 22 8 3947 21 9 3555 18 10 3658 19 6 35

-8 6.8-35 6.0- 1 5.8-16 6.6

1 5.913 6.1

-5 7.217 6.214 6.76 6.79 6.2

12 6.513 6.312 5.914 5.9

1 6.5

1 1 2 0.5 7.44 29.3 145 3.2 1091 1 2 0.51 1 2 0.5 7.45 28.8 144 3.3 1071 1 2 0.51 1 2 0.5 7.39 27.9 144 3.5 1081 1 2 0.51 1 2 0.5 7.39 27.2 143 3.8 1071 1 2 0.51 1 4 0.7 7.40 27.5 143 4.1 1061 1 4 0.7 7.35 27.4 143 4.4 1061 1 4 0.71 1 4 0.7 7.38 27.3 141 4.3 1051 1 4 0.7 7.37 26.3 142 4.1 1051 1 4 0.7 7.41 27.0 139 4.8 1051 1 4 0.7 7.39 27.5 140 4.7 1031 1 4 0.7

7.36 28.0 142 4.3 104

mEq (- 189 mEqcorrected for N), and nitrogen unmeasured anions [ (Na + K) - (Cl + HCO3) I

- 23.6 g, respectively. Average plasma electrolyte 16. Average blood pH was 7.45, creatinine 1.2concentrations were (mEq/liter): sodium 139, mg/100 ml, and hematocrit 48%o. Detailed datachloride 89, potassium 3.1, bicarbonate 37.1, and for a representative study are given in Table II,

48

52

46

38

1.0

1.1

1.0

1.0

1.11.2

1.00.91.0

35

39

44

44


Id SOWCHWRIDE

GASTRICDRAINAGE

iI4

- a -

I

DiET (5mmo/es/doy) - *

A ,

I

I

I A

-40

35

130

+200

.0

-100-+300++2001+100

0

2+000

-+ 500. 0

+500+| 0

J-5000 5 10 15 20 25 30 35 40 45 50

DAYSFIG. 2. PLASMA COMPOSITION AND ELECTROLYTEBALANCE IN A REPRESENTATIVESTUDY DESIGNED TO

EVALUATE THE INFLUENCE OF DEOXYCORTICOSTERONEACETATEON THE CORRECTIONOF GASTRIC ALKALOSISBY ADMINISTRATION OF SODIUM CHLORIDE (SUBJECT M.L.). Note that the scale used in plotting potas-sium balance is different from that used for sodium and chloride.

Plasma values and cumulative balance data for twosubjects are presented in Figs. 1 and 2. The re-

sponse to aldosterone (whether given at 4- or 8-hrintervals) and to DOCAwas not significantly dif-ferent and will, therefore, be treated together inthe remainder of Results. Throughout Resultsthe term "significant" is used to describe a changewhich has a P value of 0.02 or less.

Steroid period

Acid-base balance. During the 5-7 days of ster-oid administration there was an average increase

in plasma bicarbonate of 1.8 mEq/liter, to an av-

erage final value of 38.9 mEq/liter (Table III).Average blood pH was unchanged from the pre-ceding period. If we use as control values the ex-cretion on the last 4 days of the postdrainage pe-riod, net acid excretion showed no significantchange from control (control daily net acid excre-tion averaged .43 mEq and ranged from 34 to 52mEq).

Sodium and potassium. The seven subjectsreceiving the sodium phosphate supplement re-

tained an average of 133 mEq of sodium and lostan average of 152 mEq of potassium (120 mEq

I PLASMA I 40

HCO3mEq/ liter

351

30

110

CIClqmEq/1iter 100

90 .+100

14

LIj

K1

0K -100

(corr.for N)-200

-300

+1500

No +1000+500

v

+1000

cl +5000

-500

0OAV-9ww,.M TIM----------- 11----l-lll-l-------

a -'fN'01 36r.i.61i

7

1564

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corrected for N). The other two subjects retainedan average of 12 mEq of sodium and lost an av-

erage of 47 mEqof potassium. Six of the subjectswere still in negative potassium balance by theclose of the steroid period. At that time the av-

erage potassium deficit (sum of the drainage, post-drainage, and steroid periods) was 380 mEq (280mEq corrected for N). Average plasma sodiumconcentration and plasma potassium concentrationswere not significantly different from the value atthe end of the postdrainage period.

Chloride and extracellular fluid (ECF) volume.The urine remained virtually chloride free; mean

chloride balance was + 27 mEq and plasma chlo-ride concentration remained unchanged at 89 mEq/liter. Average (ECF) volume increased by 0.3liter.

Steroid plus salt period

Acid-base balance (Table III and Fig. 3).When sodium chloride was added to the dailydiet, plasma bicarbonate concentration fell over a

7-10 day interval by an average value of 9.7 mEq/liter to an average of 29.2 mEq/liter (as com-

pared to the average value of 29.9 mEq/liter im-mediately preceding gastric drainage), and bloodpH fell to an average value of 7.41, a significantreduction. In the subsequent part of the period,which ranged up to an additional 10 days, no fur-ther changes in plasma bicarbonate concentrationor blood pH occurred. The plasma bicarbonateconcentration at the end of the steroid plus salt pe-

riod was not significantly different from the valueimmediately before gastric drainage. If we uti-lize values from the last 4 days of the postdrainageperiod as a control period, there was a cumulativeincrement in bicarbonate excretion which averaged130 mEq and a suppression of titratable acid ex-

cretion which averaged 168 mEq, but there was no

consistent change in the pattern of ammonia excre-

tion. These changes defined an average cumulativenet acid excretion of - 273 mEq (range - 149 to- 402 mEq). The simultaneous changes inplasma bicarbonate concentration and in net acidexcretion for all nine subjects are shown in Fig. 3.The suppression in acid excretion noted in thisperiod appears to be sufficient to account for thefall in ECF bicarbonate concentration. However,it should be pointed out that the marked simul-taneous expansion of the extracellular volume,

TABLE III

Effects of steroids and of NaCi on the metabolic alkalosisinduced by gastric drainage

Plasma bicarbonate concentration*

Steroid NaCi,Post- plus post-

Subject Control drainage Steroid NaCI steroid

mEq/literR.A. 29.0 37.6 39.6 28.3 28.1J.S. 27.5 36.2 38.4 27.0 25.3L.B. 30.2 36.5 38.3 29.6 27.9MM.AL 29.7 37.7 38.2 31.3 28.4N.S. 29.3 36.2 36.7 28.2 27.2P.O. 30.9 36.0 38.0 28.6 27.4D.X. 31.2 39.2 41.9 32.5 28.3M.L. 29.8 36.9 40.9 30.1 28.0D.P. 31.6 37.2 38.3 27.5 28.4

Avg 29.9 37.1 38.9 29.2 27.7

* Refers to value at the end of each period.

which averaged 5.6 liters, could have (by dilution)accounted for the entire fall in extracellular bi-carbonate concentration. Chloride space calcula-tions indicated, in fact, that the total quantity ofbicarbonate in the ECF was approximately un-changed during the period. The large cumulativesuppression of acid excretion and dilution takentogether suggest that correction of alkalosis oc-curred throughout a volume far larger than theECF, i.e., presumably throughout total body water.Indeed, it can be calculated that had the reductionin renal acid excretion not occurred, the extracel-lular bicarbonate concentration would have shownlittle or no change despite the expansion of theECF.

Sodium and potassium. Sodium chloride ad-ministration led to a retention of sodium whichaveraged 895 mEq. Potassium balance was posi-tive in both subjects who did not receive the neu-tral sodium phosphate supplement (N.S. andD.P.) and averaged 95 mEq (102 mEq correctedfor N). Potassium balance averaged - 197 mEqin the seven subjects receiving the supplement.The average cumulative potassium balance fromthe beginning of gastric drainage amounted to469 mEq (349 mEq corrected for N) for all sub-jects and 560 mEq (440 mEq corrected for N)for the subjects who received sodium phosphate.

All three subjects who retained potassium dur-ing administration of steroid plus salt (D.P., N.S.,and R.A.) were excreting all ingested potassiumby the end of the period despite a continued deficitof potassium averaging 142 mEq (the latter value

1565

KASSIkER, APPLETON, CHAZAN, AND SCHWARTZ

+400

+300-

CUMULATIVE+200

NET ALKALIEXCRETION

(mEq) + 100

0

0

A -3PLASMAHCO3

(mEq/liter) 6

9

-12

*

*

8

* *@* | *

* 2*

83* t

)_

* *

*. 0:

.3.

FIG. 3. CUMULATIVE INCREMENTS IN NET ALKALI EXCRETION (SUPPRESSIONOF NET ACID EXCRETION) ANDCHANGESIN PLASMABICARBONATECONCENTRATIONDURING ADMINISTRATION OF SODIUM CHLORIDE TO SUBJECTS WITH GASTRIC ALKA-

LOSIS RECEIVING ALDOSTERONE(1.0 MG/DAY) OR DEOXYCORTICOSTERONEACETATE

(40 MG/DAY).

was estimated from subsequent potassium reten-tion in the poststeroid period, see below).Plasma potassium concentration at the end of thesteroid plus salt period averaged 3.3 mEq/liter.

Chloride and ECFvolume. Mean chloride bal-ance averaged + 944 mEq, and plasma chlorideconcentration increased by 18 mEq/liter to a finalaverage of 107 mEq/liter. Of the 944 mEq re-

tained, 267 mEq represented "selective" chlorideretention [Cl - (Na/1.3)]. During the periodthere was a large expansion of the extracellularvolume which averaged 5.6 liters (see above).The final extracellular volume in this period was

approximately 5 liters above theon a low salt diet.

control values

Poststeroid period

Acid-base balance. When steroid administra-tion was discontinued, there was a significant fallin plasma bicarbonate concentration which aver-

aged 1.5 mEq/liter, to a final average value of27.7 mEq/liter (see Table III). Average bloodpH remained virtually unchanged at 7.39. A sup-

pression of net acid excretion averaging 234 mEqwas noted during this period. Almost one-half of

1566

O 2 4 6 8 10 12 14 16 18

.-3.*~~~~0:*~~~~ 0

3 .

@~~~0 **

L_~~~~~ S*e@ *0 * * * * 2

t 1 . 1

00

0

.

0

0


this quantity was accounted for by a diuresis ofECF which occurred after cessation of steroid ad-ministration. After the diuresis had ceased, therewas a continued suppression of acid excretionwhich averaged 20 mEq/day. This continuedsuppression of renal acid excretion, at a time whenno further change in plasma bicarbonate concen-tration was occurring, suggests that acid produc-tion may have been suppressed during sodiumchloride administration.

Sodium and potassium. A sodium diuresis, thatbegan on the 1st or 2nd day after discontinuanceof steroid administration, led to a loss of sodiumwhich averaged 430 mEq. Urinary potassiumexcretion fell in all subjects, leading to a reten-tion of potassium which averaged 253 mEq (237mEq corrected for N). In each of the subjectsfollowed until potassium excretion reached intakelevels, i.e., until potassium balance was restored,the plasma potassium concentration rose to normal.The four subjects (D.W., D.P., M.L., and L.B.)with the longest poststeroid periods (9-16 days)retained an average of 370 mEqof potassium, cor-rected for N. The largest retention of potassium(689 mEqor 638 mEqcorrected for N) is shownin Fig. 2. It is likely, of course, that some portionof the estimated positive electrolyte balances at thecompletion of each of these lengthy studies was theresult of a systematic error introduced by unmea-sured skin losses (11, 12).

Chloride and ECF volume. Chloride excretionincreased promptly and the cumulative chloridebalance averaged - 135 mEq. However, by vir-tue of the even larger sodium loss, there was, ineffect, a selective chloride retention [Cl - (Na/1.3)] which averaged 196 mEq. Plasma chlorideconcentration remained virtually unchanged. Theextracellular volume contracted by an average of0.9 liter and calculated total extracellular bicar-bonate fell by an average of 60 mEq.

Miscellaneous24-hr creatinine clearances were essentially un-

changed except for a rise of approximately 20%in the steroid plus salt period and a fall to controllevels at the end of the poststeroid period. Aver-age plasma phosphate values were unchangedthroughout. Body weight declined graduallythroughout the study (with the exception of thesteroid plus salt period) probably as the result of a

large cumulative negative nitrogen balance whichaveraged 38.5 g. Stool electrolytes were virtuallyconstant (sodium 1 mEq, chloride 1 mEq, and po-tassium 6 mEq/day), the only significant changebeing a rise in stool potassium to 14 mEq/day dur-ing the steroid plus salt period.

Discussion

A considerable body of evidence suggests thataldosterone has an important influence on acid-baseregulation, i.e., that excessive quantities of aldos-terone play a significant role in both the genesisand maintenance of metabolic alkalosis (13-16).This view has evolved largely from the findingthat patients with primary aldosteronism fre-quently demonstrate a persistent metabolic alka-losis despite a normal dietary intake of sodium,potassium, and chloride. Indeed, the occasionalfinding of saline-resistant alkalosis in the absenceof primary hyperadrenalism, particularly in thesurgical patient (17-21), has raised the pos-sibility that an elevated bicarbonate threshold mayresult solely as the consequence of a high rate ofaldosterone secretion (13, 14).

There are, on the other hand, several lines ofevidence arguing against a major role of aldos-terone in metabolic alkalosis. First, the adminis-tration of adrenal steroids (such as DOCA) toman ingesting normal or low salt diets often hasno effect on plasma bicarbonate concentration (4)or elevates it only slightly (5).2 Second, meta-bolic alkalosis is not a universal finding even inprimary aldosteronism; approximately one-fourthto one-third of patients with this disease are notalkalotic despite markedly elevated rates of aldos-terone secretion or excretion (1-3). Finally,spontaneously occurring metabolic alkalosis is notordinarily seen in disorders characterized by sec-ondary hyperaldosteronism such as cirrhosis ormalignant hypertension, even though the rate ofaldosterone secretion is often equal to or higherthan that in primary aldosteronism (25-27).

2 Administration of steroids such as DOCA to ani-mals has long been known to induce persistent metabolicalkalosis. However, in such studies, severe alkalosishas been produced only when a diet of special composi-tion is fed, e.g., deficient in potassium and containingadded alkali (22-24). Neither of these dietary condi-tions is ordinarily encountered in patients with eitherprimary or secondary aldosteronism.

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TABLE IV

Aldosterone secretion rates before and after the inductionof gastric alkalosis*

Aldosterone secretion rates Average plasma composition

Subject Control Alkalosis Control Alkalosis

pg/dayR.A. 479 229 Na, 138 138

mEqiliterJ.S. 542 173 K, 4.3 3.1

mEqlliterN.S. 703 504 Cl, 98 89

mEqiliterM.L. t 190 HCO3, 29.4 37.1

mEqiliterG.C.§ 311 202 pH 7.37 7.44

* All measurements were made on the last day of thecontrol period and again on the last day of the postdrainageperiod (called "alkalosis" in this table). Cumulativebalance data for these subjects are given in Table I.

t A control value is not available for this study becausethe fraction of the 24 hr urine collection intended foraldosterone analysis was inadvertently discarded.

§ G.C. is not included in Tables I and III because, sub-sequent to the aldosterone secretion studies, he was sub-jected to a different experimental protocol. Cumulativebalance data in this subject for the gastric drainage andpostdrainage periods were: Na, 12 mEq; Cl, -204 mEq;K (corr. for N), -178 mEq.

The role of aldosterone in the genesis and main-tenance of alkalosis thus remains uncertain andfurther investigation has been hampered by thefact that there is no clinical setting in which theproblem can be examined in a controlled and sys-tematic fashion. Accordingly, in the present in-vestigation, the model of selective depletion of hy-drochloric acid was chosen for study because thealkalotic state has been well characterized and be-cause complicating factors such as extrarenal de-pletion of sodium, water, and potassium can beavoided (6).

The study has demonstrated, first, that the in-duction of gastric alkalosis by selective depletionof hydrochloric acid leads to a reduction ratherthan to a rise in the rate of aldosterone secretion.Aldosterone secretion, which was in the range of300-700 jug/day (normal values for a low saltintake) before induction of alkalosis, fell to ap-proximately 200 ug/day when plasma bicarbonatehad reached a new steady state at a concentrationaveraging 37 mEq/liter (Table IV). The ex-planation for this change is not certain but it seemslikely that the loss of potassium, which averaged170 mEq for these subjects, was responsible (28,29). Presumably the potassium depletion more

than offsets any stimulatory effect to aldosteronesecretion which may have resulted from the con-comitant contraction of ECF volume. A possiblerole of the alkalosis per se in reducing aldosteronesecretion cannot, of course, be excluded. In anyevent, it is evident that an elevated rate of aldos-terone secretion is not a prerequisite for the de-velopment or maintenance of gastric alkalosis.

The second aim of the study was to examine theinfluence of an excess of salt-active steroid on theability of sodium chloride to restore normal acid-base equilibrium. Each day the subject was giveneither 1000 ug of aldosterone or 40 mg of DOCAin divided doses, and after several days the dietwas supplemented with 2 mmoles of sodium chlo-ride per kg. The dosage of aldosterone waschosen to equal or exceed the secretory rate whichoccurs in the great majority of patients with pri-mary, aldosteronism (27, 30). The dosage ofDOCAwas chosen to produce an even largersteroid effect, 40 mg of DOCAbeing roughlyequivalent to 1500 Mug of aldosterone in its bio-logic activity (31). In all respects the effects ofthe two steroids on the alkalotic subjects haveproved to be the same. The results show that,just as in previous studies in which salt was ad-ministered without concomitant administration ofsteroid (8, 9), there was a progressive fall inplasma bicarbonate concentration to normal levels;average plasma bicarbonate concentration fell from39 to 29 mEq/liter in association with a rise inurine pH and a striking suppression of renal acidexcretion (Fig. 3). The administration of a so-dium phosphate supplement, a measure known toenhance the development of alkalosis in animalsreceiving DOCA(32), failed to prevent correctionof the alkalosis; the subjects who received thesupplement demonstrated the same changes inacid-base equilibrium as those who did not. Con-tinued administration of steroid, for as long as 10days after plasma bicarbonate concentration hadreached a new steady state, was not accompaniedby any further significant change in plasma bi-carbonate concentration (Figs. 1 and 2).

A notable feature of the corrective phase wasthe dissociation between the effects of sodiumchloride on acid-base equilibrium and those on po-tassium balance. Despite the prompt reduction inplasma bicarbonate concentration and the fall innet acid excretion, there was usually little or no

1568


retention of potassium; in fact, with one excep-tion, all subjects receiving a sodium phosphatesupplement demonstrated a continued loss of po-tassium which increased their total potassiumdeficits to a final range of 400-500 mEq (TableI). Even the subjects on a diet free of sodiumphosphate, though they retained potassium, alsoremained somewhat potassium depleted, full repairof the deficit occurring only after withdrawal ofthe steroid. These findings are not only of physio-logic interest but also demonstrate that, contraryto usual beliefs, the combination of moderately se-vere potassium deficiency and marked aldosteroneexcess does not preclude correction of metabolicalkalosis.

Although the experimental findings are clear,the explanation for the observed results is less ap-parent. Several lines of conjecture seem worthyof consideration, however. It has recently beendemonstrated that a significant, sustained in-crease in the rate of bicarbonate reabsorption willoccur if, in a salt-restricted individual, a reductionin chloride availability diminishes the supply ofreabsorbable anion (6, 9, 33). Under such cir-cumstances continued conservation of the filteredsodium load is accomplished by an increase in thefraction of sodium reabsorbed by exchange withcation. The resultant alkalosis persists until theprovision of chloride (as either the sodium or po-tassium salt) permits restoration of a normal rateof sodium-hydrogen exchange (7-9, 33, 34). Thepresent observations could be interpreted as indi-cating that despite the presence of an excess ofsteroids, chloride retains its ability to reduce therate of sodium-hydrogen exchange. The contin-ued high rate of sodium-potassium exchangewould indicate, according to this thesis, a selectivestimulatory effect of aldosterone on the potas-sium secretory mechanism which is not influencedby chloride. It is alternatively possible, that distalexchange of sodium for both hydrogen and po-tassium is maintained at a high level by the al-dosterone effect and that chloride exerts its effectmore proximally by permitting reabsorption ofsodium chloride in place of sodium bicarbonate.According to this thesis, a resultant saturation ofthe distal exchange mechanism with bicarbonateleads to alkalinization of the urine and a suppres-sion of net acid excretion. Such a sequence ofevents would also be compatible with the finding of

continued potassium loss during correction ofalkalosis.

An additional hypothesis which might accountfor our findings is that chloride availability, bypermitting retention of sodium and expansion ofthe extracellular volume, depresses proximal bi-carbonate reabsorption. The resulting increase indelivery of alkali to the distal nephron could, asmentioned earlier, lead to increased alkali excre-tion even in the presence of a continued high rateof distal hydrogen ion exchange. According tothis theory, chloride, though critical to correctionof the alkalosis, acts indirectly through volumechanges rather than by a direct effect on the ex-change process. This latter possibility is sug-gested by the recent report that expansion of theECF depresses proximal bicarbonate reabsorptionin normal rats (35) and induces an alkali diuresisin the alkalotic dog (36). The quantitative sig-nificance of the change in volume and the changein chloride concentration in the alkalotic subjectingesting sodium or potassium chloride remainsan area for further study.

The possibility must also be considered thatthe small rise in glomerular filtration rate whichoccurred during correction with sodium chloridecould have led to less effective bicarbonate con-servation. It should- be noted, however, that simi-lar increments in glomerular filtration rate in-duced in the dog by meat feeding (37) and in manby the administration of DOCAand sodium chlo-ride (38) do not lead to significant reductions inbicarbonate reabsorption or in plasma bicarbonateconcentration (4, 37). It is also of interest thatin our study the filtered load of bicarbonate (asestimated from 24-hr creatinine clearances) fellrather than rose during the period of alkalidiuresis.

The studies reported here raise certain impor-tant questions about the role of aldosterone in thealkalosis of primary aldosteronism. On the onehand, it is evident that aldosterone, when given tothe alkalotic subject, does induce a small rise inbicarbonate concentration (approximately 2.0mEq/liter) and that this slight increment persistseven after the gastric alkalosis is erased by ad-ministration of sodium chloride. More important,however, it is evident that this aldosterone effectcould account for only a small fraction of the risein plasma bicarbonate concentration seen in many

1569


patients with primary aldosteronism (27, 30).What then is the explanation for the acid-basedisorder in primary aldosteronism? One possi-bility deserving consideration is that a longer pe-

riod of exposure to aldosterone is required thanthat which has been employed in both the presentand previous studies. The administration ofDOCAfor as long as 11 days usually producesno elevation in plasma bicarbonate concentration(4), and even when DOCAis given for as longas 2 months bicarbonate concentration increasesfrom a control of 24 mEq/liter to a final valueof only approximately 29 mEq/liter (5). A sec-

ond possibility is that other steroids secreted bypatients with primary aldosteronism, such as cor-

ticosterone or DOCA (30, 39), are responsiblefor the development of alkalosis. In fact, it hasrecently been suggested that excessive secretion ofdeoxycorticosterone may be specifically responsiblefor the alkalosis encountered in hyperadrenocorti-cism (39). Our studies do not support such a

role for DOCAbut do not rule out the remote

possibility that the combined action of two steroids(e.g., DOCAplus aldosterone) is required to pro-

duce the acid-base disturbance. Finally, it is notclear whether a contracted ECF volume, as in our

studies, may modify the renal response to aldos-terone and lead to a result different from thatseen with the expanded ECF volume which ischaracteristic of primary aldosteronism. Conceiv-ably, hormonal or intrarenal hemodynamic changesin the expanded state may be required for aldos-terone to produce and sustain a metabolic alkalo-sis. This entire problem obviously requires fur-ther exploration.

Acknowledgments

We wish to express our appreciation to the CibaPharmaceutical Co., Summit, N. J., for the generous

supply of aldosterone and to Dr. James C. Melby whokindly measured the aldosterone secretion rates in hislaboratory.

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